Patients who experience significant pain as the result of, for example, a serious traumatic injury, a surgical procedure, or chronic illness (e.g., cancer), require relief through strong prescription medication. Opiate drugs are a class of pain-relieving prescription medications frequently used in the treatment of a variety of acute and chronic, moderate to severe, pain. Examples include natural opiates such as morphine, codeine, and thebaine; semi-synthetic opioids such as hydromorphone, hydrocodone, oxycodone, oxymorphone, diacetylmorphine (heroin), nicomorphine, dipropanoylmorphine, benzylmorphine, ethylmorphine, buprenorphine and morphine glucuronides (including the 3- and 6-glucuronide); and fully synthetic opioids such as alfentanil, fentanyl, remifentanil, sufentanil, trefentanil, pethidine, methadone, tramadol and dextropropoxyphene.
The World Health Organization's guidelines recommend that two strong opioids should not be co-administered, presumably because it is generally thought that all opioids exert their analgesic effects through the same receptor mechanisms in the central nervous system (CNS). See World Health Organization, Cancer Pain Relief and Palliative Care, Geneva: WHO 1990. Studies have shown, however, that the antinociceptive (also termed analgesic) effects of structurally related morphine and oxycodone are differentially antagonized by naloxonazine (a selective μ-opioid receptor antagonist) and nor-BN1 (a κ-selective opioid antagonist), respectively, indicating that they produce antinociception through different opioid receptor mechanisms. See Ross et al., Pain 1997, 73, 151-57. The opioid receptor is believed to have four receptor subtypes named μ-opioid receptor (MOR), σ-opioid receptor (SOR), κ-opioid receptor (KOR) and δ-opioid receptor (DOR). The biochemical and cellular effects of morphine are mediated through the MOR, found in high density within the CNS.
It has been found that co-administration to rats of sub-antinociceptive (also termed sub-analgesic) doses of morphine with sub-antinociceptive doses of oxycodone results in synergistic levels of antinociception. See Ross et al., Pain 2000, 84, 421-28. Animals that received the sub-antinociceptive doses of morphine with sub-antinociceptive doses of oxycodone were similar to placebo-injected control animals with respect to CNS side effects. See id at 424-25. Animals that received equipotent doses of either opioid alone were more sedated as compared to the control animals. See id at 425-26.
Synergistic analgesic effects of orally co-administering morphine and oxycodone at a 3:2 ratio have been demonstrated in patients (see, e.g., U.S. Pat. No. 6,310,072 and U.S. Publication Nos. 2005/0053659, 2007/0031489, 2009/0291975 and U.S. application Ser. No. 12/567,209). However, efficacy of treating pain by co-administering morphine and oxycodone is dependent, at least in part, on the quantity that is administered. For example, administration of a dosage of morphine and oxycodone will not produce analgesia if the quantity administered is too low. The quantity of morphine and oxycodone administered may also play a role in the occurrence of side effects that are common to opioids, such as nausea, vomiting, drowsiness, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention, hypotension, respiratory depression and bladder dysfunction. Moreover, the onset of tolerance to the therapeutic effects of the drugs, as well as the initiation of physical dependence, may occur with daily administration of opioids; the extent of such tolerance or physical dependence is dependent in part on the quantity of opioids administered. Therefore, it is important to determine an effective oral dosing regimen for co-administering morphine and oxycodone in order to effectively and safely treat pain.
The determination of the appropriate quantity of morphine and oxycodone to administer is especially important for patients recovering from a serious traumatic injury or a surgical procedure. These patients are often treated for pain initially by IV administration of an opioid drug such as morphine. Once these patients leave the hospital or surgical center and are no longer under medical supervision, they must receive the opioid drugs by a different route (e.g., orally) since repeated IV dosing is no longer practical. In the past, doctors have often estimated the necessary oral dose of some drugs following IV administration, but such practice often results in either over-medication, which can lead to adverse side effects, or under-medication, which can result in ineffective pain management. Also, physicians often consult equianalgesic tables before opioid rotation or conversion to determine a new safe starting dose appropriate for adequate pain control. Unfortunately, there are wide and clinically important differences in published opioid equianalgesic ratios. See Shaheen et al., J. Pain Symptom. Manag., 38:3 (2009) 409-16. Thus, there is a need for a method of converting doses of intravenously administered opioids to an oral opioid dose that effectively manages the patient's pain and at the same time reduces or eliminates the problems associated with over- or under-medication. In particular, there is a need for a method of converting doses of intravenously administered opioid to orally co-administered morphine-oxycodone combination in a weight ratio of about 3:2